scholarly journals Loss of Mitochondrial Localization of Human FANCG Causes Defective FANCJ Helicase

2020 ◽  
Vol 40 (23) ◽  
Author(s):  
Jagadeesh Chandra Bose K ◽  
Bishwajit Singh Kapoor ◽  
Kamal Mandal ◽  
Shubhrima Ghosh ◽  
Raveendra B. Mokhamatam ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Fanconi Anemia ◽  
Protein G ◽  
Repair Pathway ◽  
Mitochondrial Localization ◽  
Iron Sulfur Cluster ◽  
Iron Sulfur ◽  
Damage Repair ◽  
N Terminus ◽  
Sulfur Containing

ABSTRACT Fanconi anemia (FA) is a unique DNA damage repair pathway. To date, 22 genes have been identified that are associated with the FA pathway. A defect in any of those genes causes genomic instability, and the patients bearing the mutation become susceptible to cancer. In our earlier work, we identified that Fanconi anemia protein G (FANCG) protects the mitochondria from oxidative stress. In this report, we have identified eight patients having a mutation (C.65G>C), which converts arginine at position 22 to proline (p.Arg22Pro) in the N terminus of FANCG. The mutant protein, hFANCGR22P, is able to repair the DNA and able to retain the monoubiquitination of FANCD2 in the FANCGR22P/FGR22P cell. However, it lost mitochondrial localization and failed to protect mitochondria from oxidative stress. Mitochondrial instability in the FANCGR22P cell causes the transcriptional downregulation of mitochondrial iron-sulfur cluster biogenesis protein frataxin (FXN) and the resulting iron deficiency of FA protein FANCJ, an iron-sulfur-containing helicase involved in DNA repair.

scholarly journals Despite of DNA repair ability the Fanconi anemia mutant protein FANCGR22P destabilizes mitochondria and leads to genomic instability via FANCJ helicase

2020 ◽  
Author(s):  
Jagadeesh Chandra Bose K ◽  
Bishwajit Singh Kapoor ◽  
Kamal Mondal ◽  
Subhrima Ghosh ◽  
Raveendra B. Mokhamatam ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Repair ◽  
Genomic Instability ◽  
Fanconi Anemia ◽  
Mutant Protein ◽  
Protein G ◽  
Repair Pathway ◽  
Mitochondrial Localization ◽  
Damage Repair ◽  
Repair Ability

SummaryFanconi anemia (FA) is a unique DNA damage repair pathway. Almost twenty-two genes have been identified which are associated with the FA pathway. Defect in any of those genes causes genomic instability, and the patients bear the mutation become susceptible to cancer. In our earlier work, we have identified that Fanconi anemia protein G (FANCG) protects the mitochondria from oxidative stress. In this report, we have identified eight patients having mutation (C.65G>C; p.Arg22Pro) in the N-terminal of FANCG. The mutant protein hFANCGR22P is able to repair the DNA and able to retain the monoubiquitination of FANCD2 in FANCGR22P/FGR22P cell. However, it lost mitochondrial localization and failed to protect mitochondria from oxidative stress. Mitochondrial instability in the FANCGR22P cell causes the transcriptional down-regulation of mitochondrial iron-sulphur cluster biogenesis protein Frataxin (FXN) and resulting iron deficiency of FA protein FANCJ, an iron-sulphur containing helicase involved in DNA repair.

scholarly journals The Fanconi anemia DNA damage repair pathway in the spotlight for germline predisposition to colorectal cancer

2016 ◽  
Vol 24 (10) ◽  
pp. 1501-1505 ◽  
Author(s):  
Clara Esteban-Jurado ◽  
◽  
Sebastià Franch-Expósito ◽  
Jenifer Muñoz ◽  
Teresa Ocaña ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Fanconi Anemia ◽  
Dna Damage Repair ◽  
Repair Pathway ◽  
Damage Repair

scholarly journals Endogenous formaldehyde scavenges cellular glutathione resulting in cytotoxic redox disruption

2020 ◽  
Author(s):  
Carla Umansky ◽  
Agustín Morellato ◽  
Marco Scheidegger ◽  
Matthias Rieckher ◽  
Manuela R. Martinefski ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Repair ◽  
Fanconi Anemia ◽  
Redox Homeostasis ◽  
Thiol Group ◽  
Cellular Damage ◽  
Repair Pathway ◽  
Cellular Redox ◽  
Redox Active ◽  
Development And Aging

AbstractFormaldehyde (FA) is a ubiquitous endogenous and environmental metabolite that is thought to exert cytotoxicity through DNA and DNA-protein crosslinking. We show here that FA can cause cellular damage beyond genotoxicity by triggering oxidative stress, which is prevented by the enzyme alcohol dehydrogenase 5 (ADH5/GSNOR). Mechanistically, we determine that endogenous FA reacts with the redox-active thiol group of glutathione (GSH) forming S-hydroxymethyl-GSH, which is metabolized by ADH5 yielding reduced GSH thus preventing redox disruption. We identify the ADH5-ortholog gene in Caenorhabditis elegans and show that oxidative stress also underlies FA toxicity in nematodes. Moreover, we show that endogenous GSH can protect cells lacking the Fanconi Anemia DNA repair pathway from FA, which might have broad implications for Fanconi Anemia patients and for healthy BRCA2-mutation carriers. We thus establish a highly conserved mechanism through which endogenous FA disrupts the GSH-regulated cellular redox homeostasis that is critical during development and aging.

scholarly journals Catalytic Intermediate Crystal Structures of Cysteine Desulfurase from the Archaeon Thermococcus onnurineus NA1

Archaea ◽  
2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Thien-Hoang Ho ◽  
Kim-Hung Huynh ◽  
Diem Quynh Nguyen ◽  
Hyunjae Park ◽  
Kyoungho Jung ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Elemental Sulfur ◽  
Catalytic Mechanism ◽  
Cysteine Desulfurase ◽  
Thermococcus Onnurineus Na1 ◽  
Iron Sulfur Cluster ◽  
Terminal Electron Acceptor ◽  
Iron Sulfur ◽  
Angle Rotation ◽  
Sulfur Containing

Thermococcus onnurineus NA1 is an anaerobic archaeon usually found in a deep-sea hydrothermal vent area, which can use elemental sulfur (S0) as a terminal electron acceptor for energy. Sulfur, essential to many biomolecules such as sulfur-containing amino acids and cofactors including iron-sulfur cluster, is usually mobilized from cysteine by the pyridoxal 5′-phosphate- (PLP-) dependent enzyme of cysteine desulfurase (CDS). We determined the crystal structures of CDS from Thermococcus onnurineus NA1 (ToCDS), which include native internal aldimine (NAT), gem-diamine (GD) with alanine, internal aldimine structure with existing alanine (IAA), and internal aldimine with persulfide-bound Cys356 (PSF) structures. The catalytic intermediate structures showed the dihedral angle rotation of Schiff-base linkage relative to the PLP pyridine ring. The ToCDS structures were compared with bacterial CDS structures, which will help us to understand the role and catalytic mechanism of ToCDS in the archaeon Thermococcus onnurineus NA1.

scholarly journals Dimers of glutaredoxin 2 as mitochondrial redox sensors in selenite-induced oxidative stress

Metallomics ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1241-1251 ◽  
Author(s):  
Valeria Scalcon ◽  
Federica Tonolo ◽  
Alessandra Folda ◽  
Alberto Bindoli ◽  
Maria Pia Rigobello
Keyword(s):  
Oxidative Stress ◽  
Iron Release ◽  
Iron Sulfur Cluster ◽  
Sulfur Cluster ◽  
Iron Sulfur ◽  
Redox Sensors

Grx2 coordinates an iron–sulfur cluster, forming inactive dimers. In mitochondria, Grx2 monomerization, after oxidative stress, determines iron release triggering apoptosis.

scholarly journals The iron-sulfur cluster assembly network component NARFL is a key element in the cellular defense against oxidative stress

2015 ◽  
Vol 89 ◽  
pp. 863-872 ◽  
Author(s):  
Monique V. Corbin ◽  
Davy A.P. Rockx ◽  
Anneke B. Oostra ◽  
Hans Joenje ◽  
Josephine C. Dorsman
Keyword(s):  
Oxidative Stress ◽  
Cluster Assembly ◽  
Iron Sulfur Cluster ◽  
Sulfur Cluster ◽  
Cellular Defense ◽  
Iron Sulfur ◽  
Network Component

Superoxide-Driven Aconitase FE-S Center Cycling

1997 ◽  
Vol 17 (1) ◽  
pp. 33-42 ◽  
Author(s):  
Paul R. Gardner
Keyword(s):  
Mammalian Cells ◽  
Oxidant Stress ◽  
Iron Sulfur Cluster ◽  
Cycle Enzyme ◽  
Reactive Iron ◽  
Iron Sulfur ◽  
Iron Sulfur Center ◽  
Cyclical Process ◽  
Electron Carriers ◽  
Sulfur Containing

O−2 produced by the autoxidation of respiratory chain electron carriers, and other cellular reductants, inactivates bacterial and mammalian iron-sulfur-containing (de)hydratases including the citric acid cycle enzyme aconitase. Release of the solvent-exposed iron atom and oxidation of the [4Fe-4S]2+ cluster accompanies loss of catalytic activity. Rapid reactivation is achieved by iron-sulfur cluster reduction and Fe2+ insertion. Inactivation-reactivation is a dynamic and cyclical process which modulates aconitase and (de)hydratase activities in Escherichia coli and mammalian cells. The balance of inactive and active aconitase provides a sensitive measure of the changes in steady-statO−2 levels occuring in living cells and mitochondria under stress conditions. Aconitases are also inactivated by other oxidants including O2, H2O2, NO., and ONOO− which are associated with inflammation, hyperoxia and other pathophysiological conditions. Loss of aconitase activity during oxidant stress may impair energy production, and the liberation of reactive iron may further enhance oxidative damage. Iron-sulfur center cycling may also serve adaptive functions by modulating gene expression or by signaling metabolic quiescence.

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